Transition metal-catalyzed site-selective C—H functionalization has been a broad and highly impactful enterprise in the fields of synthetic chemistry and materials science. A primary strategy to achieve site specificity is to employ substrates with directing capabilities that can position the catalytic complex to achieve selective bond functionalization. In terms of C(sp2)-H functionalization, this strategy has been widely executed for ortho-selective processes, as proximity effects are readily achieved. More recently, innovative approaches in directed C—H functionalization have now been achieved to attain meta-selectivity (Yang J. (2015) Org. Biomol. Chem. 13: 1930-1941; Dey et al., (2016) Org. Biomol. Chem. 14: 5440-5453). Select strategies include designer templates that orient the metal in close proximity to a meta C—H bond (Leow et al., (2012) Nature 486: 518-522; Dai et al., (2013) Am. Chem. Soc. 135: 7567-7571; Wan et al., (2013) J. Am. Chem. Soc. 135: 18056-18059; Lee et al., (2013) J. Am. Chem. Soc. 135: 18778-18781; Tang et al., (2104) Nature 507: 215-220; Bera et al., (2014) Org. Lett. 16: 5760-5763; Deng & Yu (2015) Angew. Chem. Int. Ed. 54: 888-891; Deng & Yu (2015) Angew. Chem. 127: 902-905; Chu et al., (215) ACS Cent. Sci. 1: 394-399; Li et al., (2015) Chem. Sci. 6: 5595-5600; Bera et al., (2015) Angew. Chem. Int. Ed. 54: 8515-8519; Bera et al., (2015) Angew. Chem. 127: 8635-8639; Patra et al., (2016) Chem. Commun. 52: 2027-2030; Li et al., (2016) Nat. Commun. 7: 10443; Dutta et al., (2017) ACS Catal. 7: 3162-3168), steric-controlled processes (Cho et al., (2000) J. Am. Chem. Soc. 122: 12868-12869; Cho et al., (2002) Science 295: 305-308; Murphy et al., (2007) J. Am. Chem. Soc. 129: 15434-15435; Cheng & Hartwig (2014) Science 343: 853-857), or transformations that are predicated on a specific mechanistic pathway selective for meta reactivity (Phipps & Gaunt (2009) Science 323: 1593-1597; Duong et al., (2011) Angew. Chem. Int. Ed. 50: 463-466; Duong et al., (2011) Angew. Chem. 123: 483-486; Saidi et al., (2011) J. Am. Chem. Soc. 133: 19298-19301; Hofmann & Ackermann (2013) J. Am. Chem. Soc. 135: 5877-5884; Martinez-Martinez et al., (2014) Science 346: 834-837; Li et al., (2015) J. Am. Chem. Soc. 137: 13894-13901 (Phipps & Gaunt (2009) Science 323: 1593-1597; Duong et al., (2011) Angew. Chem. Int. Ed. 50: 463-466; Duong et al., (2011) Angew. Chem. 123: 483-486; Saidi et al., (2011) J. Am. Chem. Soc. 133: 19298-19301; Hofmann & Ackermann (2013) J. Am. Chem. Soc. 135: 5877-5884; Martinez-Martinez et al., (2014) Science 346: 834-837; Li et al., (2015) J. Am. Chem. Soc. 137: 13894-13901).
A separate approach using palladium catalysis was developed by the Yu and Dong groups independently (Wang et al., (2015) Nature 519: 334-338; Dong et al., (2015) J. Am. Chem. Soc. 137: 5887-5890), where they draw inspiration from the Catellani reaction involving norbornene insertion/deinsertion (Catellani et al., (1997) Angew. Chem. Int. Ed. Engl. 36: 119-122; Catellani et al., (1997) Angew. Chem. 109: 142-145; Della Ca et al., (2016) Acc. Chem. Res. 49: 1389-1400) to achieve metalation at the meta position from an initial ortho-directed functionalization, as shown in FIG. 1. Further studies illustrated the capacity of this palladium-catalyzed process to be utilized in derivatives of phenylacetic acids, phenethyl amines, benzyl amines, anilines, and phenols (Shen et al., (2015) J. Am. Chem. Soc. 137: 11574-11577; Wang et al., (2016) J. Am. Chem. Soc. 138: 9269-9276; Wang et al., (2016) J. Am. Chem. Soc. 138: 14092-14099; Shi et al., (2016) J. Am. Chem. Soc. 138: 14876-14879; Wang et al., (2017) Angew. Chem. Int. Ed. 56: 5125-5129; Wang et al., (2017) Angew. Chem. 129: 5207-5211; Li et al., (2017) Angew. Chem. Int. Ed. 56: 6874-6877; Li et al., (2017) Angew. Chem. 129: 6978-6981; Chen et al., (2017) Angew. Chem. Int. Ed. 56: 8183-8186; Chen et al., (2017) Angew. Chem. 129: 8295-8298; Han et al., (2016) Chem. Commun. 52: 6903-6906; Ding et al., (2017) J. Am. Chem. Soc. 139: 417-425; Ling et al., (2017) Chem. Commun. 53; 2166-2169).
There has been interest in the catalytic C(sp2)-H functionalization of alcohol-based substrates, namely in the development of molecular scaffolds that can direct a metal species to a specific site (Knight et al., (2016) Chem. Sci. 7: 1982-1987; Li et al., (2016) Chem. Eur. J. 22: 13054-13058; Simmons & Hartwig (2010) J. Am. Chem. Soc. 132: 17092-17095; Lee et al., (2013) J. Am. Chem. Soc. 135, 18778-18781; Chu et al., (2015) ACS Cent. Sci. 21: 394-399; Guo et al., (2015) Org. Lett. 17: 1802-1805; Guo et al., (2015) Chem. Eur. J. 21: 17474-17478; Ren et al., (2015) Org. Lett. 17, 2696-2699; Chen et al., (2016) Chem. Commun. 52: 10241-10244; Shao et al., (2016) RSC Adv. 6: 78875-78880; Mo et al., (2014) Chem. Lett. 43: 264-271). Some efforts have focused on the design of acetal-based scaffolds that feature pyridyl or quinolinyl groups for the functionalization of arene-based alcohols (Knight et al., (2016) Chem. Sci. 7: 1982-1987). These scaffolds are readily covalently attached to alcohols, and when attached will induce ortho-selective Pd-catalyzed C—H alkenylations and arylations. These scaffolds can circumvent some of the challenges encountered in directed functionalizations with alcohol-based substrates (e.g., oxidative decomposition pathways), and the facile attachment, cleavage, and recovery methods for these scaffolds enable straightforward processing and telescoping procedures. These processes were designed for ortho-selective reactivity; an analogous development in meta-functionalizations would significantly expand the scope of this methodology.